Nanoparticles (NPs) offer noteworthy advantages in the treatment of several diseases by prompting, among other beneficial actions, site‐specific delivery of drugs. Ultra-small nanostructured lipid carriers (usNLC) are no exception. These correspond to a class of NPs composed of a blend of solid and liquid lipids, the latter usually in a higher proportion, which promote a less ordered solid lipid matrix, providing a higher drug loading capacity, drug release modulation, and improved stability in comparison with other lipid nanoparticles. Several manufacturing methods have been described for obtaining usNLC. However, an in-depth process understanding is mandatory for a comprehensive knowledge allowing NLC property control.

In the present work, the hot high-pressure homogenization method, characterized by an easy scaling-up, simplicity, and ease of handling, is used to develop highly concentrated, small-sized NLCs.

Critical process parameters (CPPs) and critical material attributes (CMAs) are assessed to address the reproducibility of the manufacturing procedure, consistency among batches, long-term stability of the formulation, drug loading capacity and drug release.

In order to acquire an enhanced understanding of this method, a multivariable analysis is herein applied to inspect how the physicochemical properties of the usNLC were influenced by the variation of CPPs. These include HPH-time, HPH-pressure, while CMAs, such as lipid concentration, are also taken into consideration. The results show that a high lipid concentration (15% w/w), with an intermediate pressure and a short time in HPH seem to be the crucial parameters for obtaining both a small particle size (<100nm) and a narrow size distribution (polydispersity index <0.2) in usNLC prepared by the hot-HPH method, without affecting zeta potential (>|30 mV|).